Marinus Vermeulen

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Perimesencephalic hemorrhage A nonaneurysmal and benign form of subarachnoid hemorrhage

We studied 28 patients with subarachnoid hemorrhage and normal angiograms. On early CT (within 5 days) in 13 cases, blood was seen mainly or only in the cisterns around the midbrain. This pattern of hemorrhage was found in only 1 of 92 patients with a ruptured aneurysm. None of the unexplained perimesencephalic hemorrhages was associated with intracerebral hematoma or intraventricular hemorrhage. The clinical features also differed from those of aneurysmal hemorrhage; loss of consciousness was rare, and after 3 months, all 13 patients had returned to normal life. The cause of this benign disorder remains elusive, but a venous or capillary source seems likely.

Prediction of delayed cerebral ischemia, rebleeding, and outcome after aneurysmal subarachnoid hemorrhage.

Using logistic regression, we analyzed the predictive value of a number of entry variables with respect to the outcome variables delayed cerebral ischemia, rebleeding, and poor outcome (death or severe disability) in patients with aneurysmal subarachnoid hemorrhage. The entry variables were clinical condition on admission (grades on the Glasgow Coma Scale, Hunt and Hess system), the amount of subarachnoid and intraventricular blood and the presence of hydrocephalus on the admission computed tomogram, and antifibrinolytic treatment with tranexamic acid. We used data from a prospectively studied population of 176 patients admitted within 72 hours after subarachnoid hemorrhage. The risk of delayed cerebral ischemia was best predicted by the amount of subarachnoid blood, intraventricular blood, and antifibrinolytic treatment irrespective of clinical condition and hydrocephalus. The site of delayed cerebral ischemia was not related to the location of the subarachnoid hemorrhage. Antifibrinolytic treatment was the only entry variable (negatively) predicting the risk of rebleeding. Death or severe disability after 3 months was best predicted by the amount of subarachnoid blood and the initial clinical condition reflected by the grade on the Glasgow Coma Scale.

Grading the amount of blood on computed tomograms after subarachnoid hemorrhage.

According to several studies, the amount of subarachnoid blood on the initial computed tomogram of patients with aneurysmal subarachnoid hemorrhage has predictive value with respect to infarction and outcome. Of several methods for assessing the amount of subarachnoid blood, none has been subjected to a study of interobserver agreement. We describe our own method, applied in previous studies, in which the amounts of blood in 10 basal cisterns and fissures and in four ventricles are graded separately. In grading single computed tomograms of 182 consecutive patients with subarachnoid hemorrhage, the agreement between pairs of three observers, studied with kappa statistics, was relatively good for individual cisterns or fissures (kappa between 0.35 and 0.65) and ventricles (kappa between 0.47 and 0.74). The Spearman rank correlation coefficients for the sum of the scores for subarachnoid and intraventricular blood were very high. Summed scores for extravasated blood are suitable as a baseline variable in follow-up studies of patients with subarachnoid hemorrhage.

Management problems in acute hydrocephalus after subarachnoid hemorrhage.

In a consecutive series of 473 patients admitted within 72 hours after a subarachnoid hemorrhage, 91 (19%) had hydrocephalus on the initial computed tomogram. Consciousness was unimpaired in 25 of the 91 (28%). In 11 more patients acute hydrocephalus developed within 1 week after subarachnoid hemorrhage. Thirty-eight (8%) of all 473 patients subsequently showed clinical deterioration because of acute hydrocephalus; 11 of these 38 had fluctuations in the level of consciousness. Of the 66 patients with acute hydrocephalus and impaired consciousness on admission, 26 (39%) spontaneously improved within 24 hours. Ventricular drainage was performed in 32 (31%) of the 102 patients with acute hydrocephalus (7% of all 473 patients). Consciousness improved after ventricular drainage in 25 (78%) of the 32 patients. Ventriculitis developed in 12 of the 24 patients with external drainage, mainly after greater than 3 days of drainage, and in none of the eight patients with an internal shunt. Among the 340 patients with aneurysmal subarachnoid hemorrhage and no long-term tranexamic acid treatment, the frequency of rebleeding in patients with ventricular drainage (43% of 23) was significantly higher than in hydrocephalic patients without drainage (15% of 52 patients; chi 2 = 5.009, p = 0.025) and patients without acute hydrocephalus (20% of 265 patients; chi 2 = 5.521, p = 0.019). We conclude that spontaneous improvement occurs in half of the patients with acute hydrocephalus and impaired consciousness on admission, which is usually apparent within 24 hours, and that the outcome of patients who need ventricular drainage will improve if rebleeding and infection after insertion of the ventricular drain can be prevented.

Long-term survival and vascular event risk after transient ischaemic attack or minor ischaemic stroke: a cohort study

BACKGROUND Determinants of survival and of risk of vascular events after transient ischaemic attack (TIA) or minor ischaemic stroke are not well defined in the long term. We aimed to restudy these risks in a prospective cohort of patients after TIA or minor ischaemic stroke (Rankin grade< or =3), after 10 years or more. METHODS We assessed the survival status and occurrence of vascular events in 2473 participants of the Dutch TIA Trial (recruitment in 1986-89; arterial cause of cerebral ischaemia). We included 24 hospitals in the Netherlands that recruited at least 50 patients. Primary outcomes were all-cause mortality and the composite event of death from all vascular causes, non-fatal stroke, and non-fatal myocardial infarction. We assessed cumulative risks by Kaplan-Meier analysis and prognostic factors with Cox univariate and multivariate analysis. FINDINGS Follow-up was complete in 2447 (99%) patients. After a mean follow-up of 10.1 years, 1489 (60%) patients had died and 1336 (54%) had had at least one vascular event. 10-year risk of death was 42.7% (95% CI 40.8-44.7). Age and sex-adjusted hazard ratios were 3.33 (2.97-3.73) for age over 65 years, 2.10 (1.79-2.48) for diabetes, 1.77 (1.45-2.15) for claudication, 1.94 (1.42-2.65) for previous peripheral vascular surgery, and 1.50 (1.31-1.71) for pathological Q waves on baseline electrocardiogram. 10-year risk of a vascular event was 44.1% (42.0-46.1). After falling in the first 3 years, yearly risk of a vascular event increased over time. Predictive factors for risk of vascular events were similar to those for risk of death. INTERPRETATION Long-term secondary prevention in patients with cerebral ischaemia still has room for further improvement.

Calcium antagonists in patients with aneurysmal subarachnoid hemorrhage A systematic review

Background and Purpose: It has been reported that nimodipine reduces the frequency of secondary ischemia and improves outcome after aneurysmal SAH, but definitive evidence concerning all available calcium antagonists is lacking. Methods: Systematic overview of randomized trials that were completed by January 1996 compared calcium antagonists with control and started treatment within 10 days after onset of subarachnoid hemorrhage (SAH) was performed. All calcium antagonists studied thus far (nimodipine, nicardipine, and AT877) were included. Results: We analyzed 10 trials totaling 2756 patients. The relative risk (RR) reduction of poor outcome (death or dependency) was 16% (95% CI, 6 to 27%) and that of case fatality was 10% (95% CI, -6 to 25%). To prevent one poor outcome, 19 (12 to 59) patients need to be treated. Calcium antagonists give a 33% (95%, CI 25 to 41) RR reduction in the frequency of ischemic neurologic deficit and a 20% (95% CI, 11 to 28) RR reduction in the frequency of CT-scan documented cerebral infarction. Eight (6 to 11) patients need to be treated to prevent one ischemic neurologic deficit. In the analyses for nimodipine only, treatment was associated with a 24% RR reduction of poor outcome (95% CI, 12 to 38). To prevent one poor outcome, 13 (8 to 30) patients need to be treated with nimodipine. The RR reduction of angiographically detected cerebral vasospasm was statistically significant for AT877 (38%; 95% CI, 17 to 54%) and nicardipine (21%; 95% CI, 6 to 34%) but not for nimodipine (9%; 95% CI, -2 to 19%). Conclusion: Calcium antagonists reduce the proportion of ischemic neurologic deficits and nimodipine improves overall outcome within 3 months of aneurysmal SAH; evidence for a reduction of poor outcome from all causes by nicardipine and AT877 is inconclusive. The intermediate factors by which nimodipine exerts its beneficial effect remain uncertain.

Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia.

Patients with aneurysmal subarachnoid hemorrhage (SAH) who experience delayed cerebral ischemia (DCI) have an increased risk of poor outcome. Delayed cerebral ischemia is considered to be caused by vasospasm. However, not all patients with DCI have vasospasm. Inversely, not all patients with vasospasm develop clinical symptoms and signs of DCI. In the past, treatments aiming at vasospasm were not successful in preventing ischemia. The purpose of this review is to give an overview of clinical data showing that DCI cannot always be attributed to vasospasm, and to present an in-depth analysis of clinical and autopsy studies on the role of microthrombosis in the pathogenesis of DCI. Clinical studies show that DCI is associated with an activation of the coagulation cascade within a few days after SAH, preceding the time window during which vasospasm occurs. Furthermore, impaired fibrinolytic activity, and inflammatory and endothelium-related processes, lead to the formation of microthrombi, which ultimately result in DCI. The presence of microthrombi is confirmed by autopsy studies. Insight in the pathophysiology of DCI is crucial for the development of effective therapies against this complication. Because multiple pathways are involved, future research should focus on drugs with pleiotropic effects.

The diagnosis of subarachnoid haemorrhage.

Lumbar puncture (LP) has for a long time been the mainstay of diagnosis in patients who presented with symptoms or signs of subarachnoid haemorrhage (SAH). At present, computed tomography (CT) has replaced LP for this indication. In this review we shall outline the reasons for this change in diagnostic approach. In the first place, there are drawbacks in starting with an LP. One of these is that patients with SAH may harbour an intracerebral haematoma, even if they are fully conscious, and that withdrawal of cerebrospinal fluid (CSF) may occasionally precipitate brain shift and herniation. Another disadvantage of LP is the difficulty in distinguishing between a traumatic tap and true subarachnoid haemorrhage. Secondly, the use of CT within the first two or three days offers a wealth of information about the origin and extent of the haemorrhage, and about the presence of early complications requiring urgent treatment. An early brain scan also serves as a baseline against which future changes can be measured. The information about the location of the haemorrhage is especially valuable in patients with SAH and a negative angiogram. This is a heterogeneous group of patients which will be discussed separately. The review continues with guidelines about the interpretation of the CSF in patients with a negative CT scan, which is the only remaining indication for LP in the diagnosis of SAH. The final paragraph points out the many pitfalls in the diagnosis of rebleeding by analysis of CSF samples, which makes serial CT scanning by far the preferred method.

Serial electrocardiographic recording in aneurysmal subarachnoid hemorrhage.

We prospectively studied serial electrocardiograms in 61 patients with aneurysmal subarachnoid hemorrhage. Electrocardiographic changes were related to the initial level of consciousness, to subsequent events, and to outcome after 3 months. All 61 patients had at least one abnormal electrocardiogram, but cardiac disease did not contribute directly to morbidity or mortality. Fast rhythm disturbances, ischemic changes, or both on the electrocardiograms were significantly correlated with poor outcome but not with specific outcome events, particularly not with rebleeding or cerebral ischemia. The Glasgow Coma Scale score on admission and the amount of cisternal and (to a lesser extent) intraventricular blood on the initial computed tomogram were also significantly correlated with poor outcome, but these factors only partially confounded the relation between electrocardiographic abnormalities and poor outcome. We conclude that in patients with aneurysmal subarachnoid hemorrhage, electrocardiographic abnormalities do not herald impending cardiac disease but indirectly reflect adverse intracranial factors. Electrocardiographic abnormalities may therefore have some independent value in predicting poor outcome.